Systemic Lupus Erythematosus (SLE) is a disease that can produce fever, rash, hair loss, arthritis, pleuritis, pericarditis, nephritis, anemia, leucopenia, thrombocytopenia and central nervous system damage. The clinical course is characterized by periods of remissions and acute or chronic relapses. Characteristic immune abnormalities, especially antibodies to nuclear and other cellular antigens, develop in patients with SLE (Schur P H, systemic lupus erythematosus, in Cecil textbook of Medicine, 22nd edition, Editors: Goldman L, Ausiello D, Saunders, USA, 2004, pp 1660-1670).
SLE occurs more frequently in women. The female to male ratio ranges from 10:1 to 15:1 in adults and in other individuals it is 8:1. Among the general population the prevalence is estimated to be 40-50 per 100,000. The cause of SLE remains unknown in spite of many observations on the involvement of genetic, immunologic, hormonal and environmental factors. SLE is primarily a disease with abnormalities of immune system regulation. These abnormalities are secondary to a loss of self tolerance, resulting in autoimmune responses. Due to decreased number of regulatory (suppressor) T cells which control the immune response, the immune response against self components increases, causing activation and proliferation of autoreactive B cells which differentiate into antibody-producing cells and make an excess of antibodies to many nuclear antigens. Anti nuclear antibodies are elevated especially to dsDNA, ssDNA, nucleoproteins and other self components. In addition, female hormones promote B-cell hyperactivity while androgens have the opposite effect. Environmental factors like microorganisms may stimulate cells in the immune system. Ultraviolet irradiation is known to exacerbate lupus skin lesions.
The pathogenesis of SLE includes many manifestations, which are mediated by antibodies. Diffuse proliferative glomerulonephritis is caused by immune complexes, which consist of nuclear antigens and antinuclear antibodies, formed in the circulations and deposited in the glomerular basement membrane or formed in situ. This activates the complement system resulting in the generation of chemotactic factors causing attraction and infiltration of leukocytes which phagocytose the immune complexes and cause the release of mediators which further perpetuate the glomerular inflammation. Deposition of immune complexes leads to chronic inflammation, fibrinoid necrosis and scarring, and renal dysfunction (Schur P H, systemic lupus erythematosus, in Cecil textbook of Medicine, 22nd edition, Editors: Goldman L, Ausiello D, Saunders, USA, 2004, pp 1660-1670). Immune complexes have been detected at the dermal-epidermal junction in skin lesions and normal skin, in the choroid plexus, pericardium and pleural cavity.
The pathological symptoms of SLE include renal disease, musculoskeletal manifestations such as arthralgia and arthritis, mucocutaneous lesions including photosensitivity, rash and discoid lesions, vascular, cardiovascular and pulmonary lesions, hematologic manifestations, gastrointestinal and neuropsychiatric disturbances, and general symptoms like sleep disturbances and depression. Drug therapy is mainly based on steroids (prednisone) and immunosuppressants (cyclophosphamide, azathioprine). The prognosis of SLE patients has improved during the last 50 years i.e. the current survival rate is approximately 90% at 10 years. Nevertheless, there are side effects of the medicaments associated with poor quality of life and, in 10% of the cases a bad prognosis is anticipated especially in CNS involvement, hypertension, azotemia and early age of onset.
U.S. Pat. No. 6,537,968 discloses a method for treating lupus erythematosus comprising administering a therapeutically effective amount of a composition containing a protease inhibitor selected from a group consisting of alpha 1-antitrypsin, secretory leukocyte protease inhibitor and alpha 2-macroglobulin.
U.S. Pat. No. 7,419,670 discloses viral protein SERP-1, SERP-1 analogs or biologically active fragments, which are useful for treating inflammatory or immune reaction associated with arthritis, systemic lupus erythematosus (SLE), multiple sclerosis (MS) and asthma. While U.S. Pat. No. 7,419,670 claims methods of treating a mammalian subject having arthritis, systemic lupus erythematosus (SLE), multiple sclerosis (MS) and asthma the polypeptides disclosed are useful only when administered in combination with an immunosuppressant.
U.S. Patent Application No. 2008/0261868 provides a method of treating a subject suffering from a disease characterized by excessive apoptosis by administering at least one serine protease inhibitor, preferably alpha 1-antitrypsin or a derivative thereof.
U.S. Patent Application No. 2008/0095806 discloses protease inhibitor composition useful for preventing and treating hyperproliferative and inflammatory mucocutaneous disorders. U.S. Patent Application No. 2008/0095806 claims methods of treating hyperproliferative and inflammatory mucocutaneous disorders comprising administering to the subject an effective amount of protease inhibitor in a pharmaceutically acceptable carrier or diluent. According to U.S. Patent Application No. 2008/0095806, the protease inhibitor is preferably a serine protease inhibitor, and more preferably alpha 1-antitrypsin including peptide fragments and derivatives thereof useful for preventing and treating hyperproliferative and inflammatory mucocutaneous. Nonetheless there is no indication of specific peptide fragments derived from alpha 1-antitrypsin.
U.S. Pat. No. 5,093,316 discloses a method and pharmaceutical compositions for treating pulmonary inflammation in pulmonary diseases comprising administering an effective amount of microcrystalline alpha-1-antitrypsin, derivatives or salts thereof.
International Patent Application No. WO 9206706 provides use of an effective amount of alpha 1-antitrypsin among other serine protease inhibitors for the prophylaxis or treatment of a mast cell-implicated disease or injury in a mammal.
U.S. Pat. No. 5,134,119 discloses a method for prophylaxis or direct treatment of mast cell implicated skin inflammation or treating the symptoms of burns in a patient comprising administering an effective amount of an analog of alpha 1-antitrypsin. While U.S. Pat. No. 5,134,119 discloses various analogs of alpha 1-antitrypsin, the polypeptides are useful for treatment of mast cell implicated skin inflammation only when methionine at position 358 is substituted with an aliphatic amino acid.
There is still an unmet need for improved medicaments for treating inflammatory and autoimmune diseases.
Severe sepsis occurs when the inflammatory reaction towards an infectious agent leads to organ dysfunction, such as trouble breathing, coagulation or other blood abnormalities, decreased urine production, or altered mental status. If the organ dysfunction of severe sepsis is low blood pressure (hypotension), or insufficient blood flow (hypoperfusion) to one or more organs (causing, for example, lactic acidosis), this condition is referred to as septic shock.
Sepsis can lead to multiple organ dysfunction syndrome (MODS) culminating in death. Organ dysfunction results from local changes in blood flow, from sepsis-induced hypotension (<90 mmHg or a reduction of ≧40 mmHg from baseline) and from diffuse intravascular coagulation, among other things.
Sepsis can be defined as the body's response to an infection caused by microorganisms or bacteria invading the body, and can be limited to a particular body region or can be widespread in the bloodstream. Sepsis is acquired quickest with infections that are developed during surgery and physical contact with someone with sepsis.
The therapy of sepsis rests on antibiotics, surgical drainage of infected fluid collections, fluid replacement and appropriate support for organ dysfunction. This may include hemodialysis in kidney failure, mechanical ventilation in pulmonary dysfunction, transfusion of blood products, and drug and fluid therapy for circulatory failure.
Most therapies aimed at the inflammation process itself have failed to improve outcome, however drotrecogin alfa (activated protein C, one of the coagulation factors) has been shown to decrease mortality from about 31% to about 25% in severe sepsis. To qualify for drotrecogin alfa, a patient must have severe sepsis or septic shock with an APACHE II score of 25 or greater and a low risk of bleeding. However, since further trials have failed to replicate this result, the use of activated protein C is controversial.
In some cases, sepsis may lead to inadequate tissue perfusion and necrosis. As this may affect the extremities, amputation may become necessary.